HIV-1 Natural Viral Suppressors are a unique cohort of patients who are able to suppress HIV-1 viral replication to extremely low levels.1
Although there have been some studies on HCV infection in LTNPs (none in the NVS or Elite controllers), these have mostly focused on response to HCV treatment and effects of a specific HCV genotype on HIV progression.6–7
The goal of this study was to characterize HCV infection in the NVS cohort, a cohort of patients all that have already demonstrated the ability to control one chronic viral infection.
Our results indicate that the NVS, as a group, demonstrate better control of HCV infection than the controls in that they had significantly higher rates of spontaneous clearance compared to race-matched historical controls of both HIV/HCV co-infected and HCV mono-infected patients. Spontaneous HCV clearance rates in various studies range from 6–80%, with a calculated mean of 26%.8–12
In African-Americans, another Baltimore-based cohort with a male preponderance reported a 9.3% clearance rate,13
which is similar to the clearance rate of 9.1% in our HCV mono-infected cohort. The NVS cohort is comprised of patients with variables traditionally associated with lower rates of spontaneous clearance of HCV, i.e male gender, African American race, intravenous drug use, and HIV infection.14
Despite this, the rates of HCV clearance in the NVS cohort was 23.3%, significantly higher than both the HIV/HCV co-infected (6.5%) and HCV mono-infected cohorts (9.1%). Recently, IL28B polymorphisms have been shown to be associated with clearance of HCV, and it remains to be seen whether this could be a potential mechanism involved in the elevated HCV clearance in the NVS group.15
Nevertheless, the ability of some NVS to successfully control 2 agents of chronic viral illness (HIV-1 and HCV), implies that a common genetic factor (controlling either innate or adaptive immunity) is responsible for the viral control in these individuals.
The only dissimilarity in the demographics of the 3 cohorts was male/female ratio (over-representation in the NVS compared to the other 2 cohorts). This is a potentially important confounder as studies have shown significantly higher clearance of HCV in females compared to males.8–12
However, when controlling for female sex, the findings of a higher clearance rate in the NVS was still statistically significant when compared to the HIV/HCV and HCV groups.
Besides the difference in HCV clearance rates, we were unable to detect any differences in HCV infection between NVS and the controls. Those NVS who developed chronic HCV infection did not control the infection better than the control groups, nor did they have less disease progression than the controls. The results demonstrated a difference between the HCV mono-infected and HIV/HCV co-infected cohorts in terms of HCV viral load and severity of liver disease by biopsy, with the NVS having values between the two groups. Although none of the results comparing the NVS to the other groups were significant, the trend implies that the NVS may have slightly less control of the HCV infection than the HCV mono-infected group, these findings tend to agree with previous studies that have shown increase HCV viral loads and HCV-related disease in HIV/HCV co-infected patients,16–23
which is presumably because of a decrease in HCV-specific CD4+ and CD8+ response in co-infected patients.24
Within the NVS cohort, there was a significant association between chronic HCV infection and immunological impairment. The CD4 count, CD4%, and CD4/CD8 ratios were lower in those with circulating Hepatitis C virus than those without. The median CD4 cell difference was 294 cells/ul (with an 11% difference in CD4%). However, it should be noted that we were unable to demonstrate a difference in the HIV-1 proviral copy numbers or frequency of viral “blips” between those NVS with and without chronic HCV. Testing with HIV-1 viral load assays with a limit of detection of 1 copy/ml may help answer this question.25
Whether this degree of immunologic impairment associated with HCV infection in the NVS will eventually have clinical significance is unknown; however, these findings add to the growing body of literature regarding the detrimental effects of HCV in patients infected with HIV. The chronic engagement of B lymphocytes by HCV in chronic infection can cause non-specific antibody production such as cryoglobulins, but it is uncertain if this may impact the course of HIV infection. Recently, one large study has shown HCV infection is a risk factor for developing AIDS-defining illness.26
Previous studies have shown a blunted CD4 response to HAART in patients with HCV infection;16,27
however, this association has not been consistently demonstrated in other studies.28
Our study may be the first to correlate the direct impact of HCV on CD4 cell count in HIV-infected patients. Although low CD4 counts in HIV negative cirrhotic patients are thought to occur secondary to splenic sequestration,29
none of the NVS have a clinical or pathologic diagnosis of cirrhosis. In addition, in the former case CD4% are preserved, but the NVS with HCV have lower CD4% and CD4/CD8 ratios, suggesting loss of CD4 rather than sequestration. The mechanism involved in the decrease in CD4 cells seen in the NVS is likely to be an increase in naive CD4 apoptosis as has been described by Nunez et al.30
In typical co-infected patients, the impact of HCV on cellular immunity may be masked by the much greater HIV-induced immunosuppression, thus cohorts such as the NVS may be more suitable for demonstrating subtle HCV-induced effects on the immune system.
Because of the inherent difficulty in identifying NVS with acute HCV, this study was cross-sectional and this has to be considered in interpreting the results. However, the NVS cohort was similarly matched to the other 2 cohorts, which strengthens the findings. All three cohorts were composed of African-Americans only, closely matched for age, route of infection (majority IDU), estimated date of infection for HCV, and HCV genotype (see ). Importantly, the median estimated date of HCV infection was similar for all three cohorts (between 1973–1975), predating potential exposure to HIV-1. Given that our cohorts were entirely composed of African-Americans, these findings may not pertain to other ethnic groups, which can have a different genetic and immunologic makeup. Further studies are needed to confirm our findings in African-Americans and other groups of patients.